Gene Summary

Gene:MACC1; MET transcriptional regulator MACC1
Aliases: 7A5, SH3BP4L
Summary:MACC1 is a key regulator of the hepatocyte growth factor (HGF; MIM 142409)-HGF receptor (HGFR, or MET; MIM 164860) pathway, which is involved in cellular growth, epithelial-mesenchymal transition, angiogenesis, cell motility, invasiveness, and metastasis. Expression of MACC1 in colon cancer (MIM 114500) specimens is an independent prognostic indicator for metastasis formation and metastasis-free survival (Stein et al., 2009 [PubMed 19098908]).[supplied by OMIM, Mar 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:metastasis-associated in colon cancer protein 1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MACC1 (cancer-related)

Li M, Wang Q, Xue F, Wu Y
DNA Cell Biol. 2019; 38(6):572-582 [PubMed] Related Publications
Pieces of evidence have shown that cytoskeleton regulator RNA (

Li Z, Guo T, Fang L, et al.
MACC1 overexpression in carcinoma‑associated fibroblasts induces the invasion of lung adenocarcinoma cells via paracrine signaling.
Int J Oncol. 2019; 54(4):1367-1375 [PubMed] Related Publications
Carcinoma‑associated fibroblasts (CAFs) are essential for initiating lung cancer cell invasion and metastasis. An elevated MACC1 expression has been implicated in the progression of lung adenocarcinoma. Hitherto, the role of MACC1 in lung adenocarcinoma‑derived CAFs remains unclear. In this study, CAFs isolated from the tissues of patients with lung adenocarcinoma expressed typical CAF markers (shown by immunohistochemical and immunofluorescence analysis) and exhibited enhanced migration and invasion abilities when co‑cultured with A549 cells in a microfluidic model. MACC1‑overexpressing CAFs not only demonstrated an increased invasion, but also exerted a promoting effect on the invasion of tumor cells. The reduced expression of MACC1 impaired the invasive ability of the CAFs. Western blot analysis and RT‑qPCR analysis demonstrated that multiple paracrine pathways were activated in the MACC1‑overexpressing CAFs. Overall, this study presents a novel role of MACC1 in CAF‑induced lung adenocarcinoma cell invasion, which possibly occurs via paracrine signaling. Furthermore, MACC1 was indicated to be a potential therapeutic target for lung adenocarcinoma.

Radhakrishnan H, Walther W, Zincke F, et al.
MACC1-the first decade of a key metastasis molecule from gene discovery to clinical translation.
Cancer Metastasis Rev. 2018; 37(4):805-820 [PubMed] Related Publications
Deciphering the paths to metastasis and identifying key molecules driving this process is one important issue for understanding and treatment of cancer. Such a key driver molecule is Metastasis Associated in Colon Cancer 1 (MACC1). A decade long research on this evolutionarily conserved molecule with features of a transcription factor as well as an adapter protein for versatile protein-protein interactions has shown that it has manifold properties driving tumors to their metastatic stage. MACC1 transcriptionally regulates genes involved in epithelial-mesenchymal transition (EMT), including those which are able to directly induce metastasis like c-MET, impacts tumor cell migration and invasion, and induces metastasis in solid cancers. MACC1 has proven as a valuable biomarker for prognosis of metastasis formation linked to patient survival and gives promise to also act as a predictive marker for individualized therapies in a broad variety of cancers. This review discusses the many features of MACC1 in the context of the hallmarks of cancer and the potential of this molecule as biomarker and novel therapeutic target for restriction and prevention of metastasis.

Jeong H, Jung J, Oh HE, et al.
Prognostic Characteristics of MACC1 Expression in Epithelial Ovarian Cancer.
Biomed Res Int. 2018; 2018:9207153 [PubMed] Free Access to Full Article Related Publications
Recent studies have shown that overexpression of metastasis-associated in colon cancer 1 (MACC1) is significantly associated with adverse prognoses of patients with different kinds of cancer. However, the exact survival effect of MACC1 on epithelial ovarian cancer (EOC) patients has not yet been established. Thus, the objective of this study was to explore the prognostic role of MACC1 mRNA in EOC by using Kaplan-Meier (KM) plotter and ONCOMINE database. Our results indicated that MACC1 mRNA high expression was significantly associated with unfavorable overall survival (hazard ratio (HR) = 1.51 (95% confidence interval (CI): 1.21 - 1.88),

Sperlich A, Balmert A, Doll D, et al.
Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer.
BMC Cancer. 2018; 18(1):998 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Even though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. We investigated in a retrospective setting whether genetic and immunological biomarkers can be applied for stratification of distant metastasis occurrence risk.
METHODS: Eighty four patients with complete resection (R0) of stage III colon cancer from two clinical centres were analysed for genetic biomarkers: microsatellite instability, oncogenic mutations in KRAS exon2 and BRAF exon15, expression of osteopontin and the metastasis-associated genes SASH1 and MACC1. Tumor-infiltrating CD3 and CD8 positive T-cells were quantified by immunocytochemistry. Results were correlated with outcome and response to 5-FU based adjuvant chemotherapy, using Cox's proportional hazard models and integrative two-step cluster analysis.
RESULTS: Distant metastasis risk was significantly correlated with oncogenic KRAS mutations (p = 0.015), expression of SASH1 (p = 0.016), and the density of CD8-positive T-cells (p = 0.007) in Kaplan-Meier analysis. Upon multivariate Cox-regression analysis, KRAS mutation (p = 0.008) and density of CD8-positive TILs (p = 0.009) were retained as prognostic parameters for metachronous distant metastasis. Integrative two-step cluster analysis was used to combine all genetic markers, allowing stratification of patient subgroups. Post-operative distant metastasis risk ranged from 31% (low-risk) to 41% (intermediate), and 57% (high-risk) (p = 0.032). Increased expression of osteopontin (p = 0.019) and low density of CD8-positive T-cells (p = 0.043) were significantly associated with unfavourable response to 5-FU.
CONCLUSIONS: Integrative biomarker analysis allows stratification of stage III colon cancer patients for the risk of metastatic disease recurrence and may indicate response to 5-FU. Thus, biomarker analysis might facilitate the use of adjuvant therapy for high risk patients.

Cui XW, Qian ZL, Li C, Cui SC
Identification of miRNA and mRNA expression profiles by PCR microarray in hepatitis B virus‑associated hepatocellular carcinoma.
Mol Med Rep. 2018; 18(6):5123-5132 [PubMed] Related Publications
The present study aimed to identify differentially expressed microRNAs (miRNAs) and mRNAs in hepatitis B virus‑associated hepatocellular carcinoma (HCC). A total of five HCC tissues and paired adjacent non‑tumor tissues were screened to identify the differentially expressed miRNAs and target mRNAs using polymerase chain reaction microarrays. The interaction between differential miRNA and mRNA expression was concurrently analyzed using bioinformatics methods. A total of 32 differentially expressed miRNAs (four upregulated miRNAs and 28 downregulated miRNAs) and 16 differentially expressed mRNAs (11 upregulated mRNAs and five downregulated mRNAs) were identified. Among these, upregulated hsa‑miRNA (miR)‑96‑5p and hsa‑miR‑18b‑5p suppressed their target mRNAs forkhead box O1 and MET transcriptional regulator MACC1 (MACC1). Downregulation of hsa‑miR‑199a‑5p led to upregulation of its target mRNAs, cyclin dependent kinase 4 and insulin like growth factor 2 (IGF2). The high‑level expression of IGF2 mRNA and cyclin E1 mRNA was due to the low‑level expression of hsa‑miR‑145‑5p, hsa‑miR‑181a‑5p, hsa‑miR‑199a‑5p and hsa‑miR‑223a‑3p, and hsa‑miR‑26a‑5p and hsa‑miR‑26b‑5p, respectively. The low‑level expression of coronin 1A mRNA and MACC1 mRNA was due to overexpression of hsa‑miR‑517a‑3p and hsa‑miR‑18a‑5p, and hsa‑miR‑18b‑5p, respectively. Numerous gene ontology terms were associated with oncogenesis. The most enriched pathways targeted by the dysregulated miRNAs and mRNAs were associated with cancer and oncogenesis pathways. The present data suggested that differential miRNA and mRNA expression is present in HCC. Thus, interactions between certain miRNAs and mRNAs may be involved in the pathogenesis of HCC.

Zhang Q, Xu P, Lu Y, Dou H
Correlation of MACC1/c-Myc Expression in Endometrial Carcinoma with Clinical/Pathological Features or Prognosis.
Med Sci Monit. 2018; 24:4738-4744 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Endometrial carcinoma (EC) is a type of female reproductive malignant tumor, the incidence of which is generally 20~30%. Multiple factors and genes are involved in the regulation of EC occurrence and progression. This study aimed to measure the expressions of MACC1 and c-Myc in EC patients to analyze their correlation with pathological features of EC. MATERIAL AND METHODS A total of 60 EC patients were recruited in the experimental group, while another cohort of 30 people with endometrial inflammatory hyperplasia was enrolled in the control group. The levels of serum MACC1 and c-Myc were measured by ELISA, and the protein expressions in EC cancer tissues, tumor-adjacent tissues, and controlled endometrial tissues were detected by immunohistochemistry (IHC). The correlation between gene expression and clinical/pathological features was then determined. RESULTS Our data indicate that the level of serum MACC1 and c-Myc in the experimental group was 1.67±0.08 ng/ml and 1.78±0.07 ng/ml, respectively, both of which were significantly higher than that of the control group (p<0.05). However, no significant difference was found among levels of serum MACC1 or c-Myc at different TNM stages (p>0.05). In cancer tissues, the positive rate of MACC1 or c-Myc was 73.3% and 78.3%, respectively, which were significantly higher than that in adjacent or control tissues (p<0.05). MACC1/c-Myc expression was correlated with TNM stage, primary infiltration grade, lymph node metastasis, and distal metastasis (p<0.05). CONCLUSIONS MACC1 and c-Myc are highly expressed in serum and tumor tissues of EC patients. Both are correlated with TNM stage, primary infiltration, and lymph node or distal metastasis, which provides a scientific basis for the development of new biomarkers for the diagnosis of endometrial carcinoma.

Zhang Q, Zhang B, Sun L, et al.
Cisplatin resistance in lung cancer is mediated by MACC1 expression through PI3K/AKT signaling pathway activation.
Acta Biochim Biophys Sin (Shanghai). 2018; 50(8):748-756 [PubMed] Related Publications
One of the major obstacles hindering the treatment of lung cancer (LC) is chemoresistance; however, its mechanism remains unclear. The overexpression of the metastasis-associated in colon cancer 1 (MACC1) gene has been demonstrated to reverse chemoresistance. In the current study, the expression of MACC1 in LC cells with cisplatin resistance (Cis-Re) was investigated. Cisplatin-resistant cell sublines (A549/CR and H446/CR) were induced by stepwise escalation of cisplatin exposure. MTS and flow cytometry assays were performed to measure cell proliferation and apoptosis, respectively. Western blot analysis and qRT-PCR assays were performed to determine the changes in signaling pathway-related protein and mRNA levels, respectively. A nude mouse xenograft model was used for in vivo experiments. Our results showed that MACC1 expression was increased in the cisplatin-resistant A549/CR and H446/CR cell lines, and the resistance was reversed with a decrease of MACC1 expression. MACC1 overexpression triggered an increase of Cis-Re, which was contrary to the effect of MACC1 down-regulation. In addition, the effect of MACC1 on Cis-Re was blocked by the inhibition of the PI3K/AKT pathway, and treatment with both cisplatin and a PI3K/AKT inhibitor effectively inhibited tumor growth in xenografts with MACC1 overexpression. In conclusion, our results revealed that MACC1 increased Cis-Re partially via the PI3K/AKT signaling pathway, suggesting that MACC1 could serve as a potential target to overcome Cis-Re. Furthermore, combination therapy could alleviate Cis-Re resulted from MACC1 overexpression in patients with LC.

Guo L, Ou S, Ma X, et al.
MACC1 silencing inhibits cell proliferation and induces cell apoptosis of lung adenocarcinoma cells through the β-catenin pathway.
Neoplasma. 2018; 65(4):552-560 [PubMed] Related Publications
It has been documented that over-expression of metastasis-associated in colon cancer-1 (MACC1) is related to poor prognosis in non-small cell lung cancer (NSCLC). This study investigates the function and underlying molecular mechanisms of MACC1 in lung adenocarcinoma. Here, we firstly employed immunohistochemistry, western blotting, real-time PCR, and online database to demonstrate that MACC1 expression was elevated in tumor tissues compared with tumoradjacent or normal tissues. Real-time PCR, CCK-8, colony formation western blotting, Hoechst staining, and flow cytometry assays then evaluated the effects of MACC1 knockdown on the cell cycle, cell proliferation and apoptosis in A549  and H1299 adenocarcinoma cells. Result highlighted that MACC1 knockdown inhibited cell proliferation, induced G0/ G1 phase arrest and promoted cell apoptosis in vitro. Mechanistic analysis revealed it also up-regulated expression levels of bax, cleaved-caspase-3 and cleaved-PARP while down-regulating cyclin D1, c-myc, bcl-2, and β-catenin expression in A549 cells. Intriguingly, up-regulation of β-catenin suppressed G0/G1 phase arrest and apoptosis in MACC1-silenced A549 cells and this was accompanied by increased levels of cyclin D1, c-myc, and bcl-2. Collectively, our results indicate that MACC1 knockdown effectively inhibited cell proliferation and promoted apoptosis of lung adenocarcinoma cells by regulating the β-catenin pathway.

Tsilimigras DI, Ntanasis-Stathopoulos I, Bagante F, et al.
Clinical significance and prognostic relevance of KRAS, BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: A systematic review of the current evidence.
Surg Oncol. 2018; 27(2):280-288 [PubMed] Related Publications
BACKGROUND: Hepatic resection is considered the optimal potentially curative treatment for colorectal liver metastases (CRLM). Following resection, up to two-thirds of patients will develop recurrence within 5-years. Genetic mutation analysis of CRLM, especially KRAS status, has been proposed as a means to guide treatment, as well as identifying patients who can derive the most survival benefit from hepatic resection.
METHODS: A systematic review of the literature was conducted the PubMed, Embase and Cochrane library through February 8th, 2018. The following algorithm was applied: "(colorectal OR rectal OR colon OR colonic) AND (liver OR hepatic) AND (metastasis OR metastases) AND (gene OR mutation OR KRAS OR BRAF OR SMAD4 OR RAS OR TP53 OR P53 OR APC OR PI3K OR MSI OR EGFR OR MACC1 OR microsatellite)."
RESULTS: From the 2404 records retrieved, 78 studies were finally deemed eligible; 47 studies reported mutational data on patients with resectable CRLM, whereas 31 studies reported on patients with unresectable CRLM. Mutational analyses were mostly performed on the CRLM specimen rather than the primary CRC. The vast majority of studies reported on the KRAS mutational status (88.5%, n = 69/78). Prevalence of KRAS mutations ranged from 25% to 52%. Most studies reported that RAS mutation was a negative prognostic factor for overall (OS) (n = 24) and recurrence-free (RFS) (n = 9) survival; a few reports noted no effect of RAS mutational status on OS (n = 4) or RFS (n = 6). Twelve studies reported on BRAF mutations with a prevalence of BRAF mutation ranging from 0 to 9.1% in resected CRLM specimens. BRAF mutation was strongly associated with a worse prognosis. TP53 and PIK3CA gene mutations did not affect long-term outcomes.
CONCLUSIONS: The biological status of each tumor provides the basis for individualized cancer therapeutics. Data on the mutational status on CRLM should be a part of multidisciplinary discussions to help inform the therapeutic approach, type of chemotherapy, as well as timing and approach of surgical resection.

Wang S, Zhang Y, Yuan S, Ji X
MicroRNA‑485 targets MACC1 and inhibits cervical cancer cell proliferation and invasion.
Mol Med Rep. 2018; 18(2):2407-2416 [PubMed] Related Publications
A large body of evidence has indicated that microRNAs (miRNAs/miRs) have essential roles in the development and progression of cervical cancer. Thus, miRNAs with dysregulated expression are potential biomarkers for cervical cancer diagnosis and prognosis. In the present study, expression levels of miR‑485 were detected in cervical cancer tissues and cell lines. The effects of miR‑485 overexpression on the proliferation and invasion of cervical cancer cells were determined with Cell Counting kit‑8 and Transwell invasion assays. The mechanisms underlying the action of miR‑485 in cervical cancer were investigated using bioinformatics analysis, a luciferase reporter assay, reverse transcription‑quantitative polymerase chain reaction and western blot analysis. In addition, the association between miR‑485 and metastasis associated in colon cancer‑1 (MACC1) in cervical cancer tissues was examined. The present study demonstrated that miR‑485 expression was significantly downregulated in cervical cancer tissues and cell lines. Reduced miR‑485 expression in patients with cervical cancer was correlated with International Federation of Gynecology and Obstetrics stage and lymph node metastasis. Furthermore, restored expression of miR‑485 significantly reduced cervical cancer cell proliferation and invasion. MACC1 was identified as a direct target gene of miR‑485 in cervical cancer. MACC1 expression was significantly upregulated in cervical cancer specimens and was inversely correlated with miR‑485 expression. Additionally, the restored expression of MACC1 eliminated the suppressive effects of miR‑485 overexpression on the proliferation and invasion of cervical cancer cells. Notably, the upregulation of miR‑485 suppressed the MET proto‑oncogene, receptor tyrosine kinase (Met)/RAC‑α serine/threonine‑protein kinase (AKT) signaling pathway. These results demonstrated that miR‑485 may perform its tumor suppressive function in cervical cancer by directly targeting MACC1 and inhibiting the Met/AKT signaling pathway. Therefore, the miR‑485/MACC1 axis may be a novel and effective therapeutic target in cervical cancer.

Ozturk E, Aksoy SA, Ugras N, et al.
Coexistence of MACC1 and NM23-H1 dysregulation and tumor budding promise early prognostic evidence for recurrence risk of early-stage colon cancer.
APMIS. 2018; 126(2):99-108 [PubMed] Related Publications
The tumor-node-metastasis (TNM) classification, the presence of a mucinous component, and signet ring cells are well-known criteria for identifying patients at a high risk for recurrence and determining the therapeutic approach for early-stage colon cancer (eCC). Nevertheless, recurrence can unexpectedly occur in some eCC cases after surgical resection. The aims of the present study were to evaluate the relation of dysregulated MACC1, c-MET, and NM23-H1 expression with the histopathological features of tumors in recurrence formation in eCC cases. A total of 100 sporadic eCC patients without poor prognosis factors were evaluated in this study. The relationship between the altered expression of MACC1, c-MET, and NM23-H1 and pathological microenvironmental features, including the presence of tumor budding and desmoplasia, were assessed. The primary outcomes, including 5-year overall survival (OS) and disease-free survival (DFS), were also measured. Compared with nonrecurrent patients, the expression level of MACC1 was 8.27-fold higher, and NM23-H1 was 11.36-fold lower in patients with recurrence during the 5-year follow-up (p = 0.0345 and p = 0.0301, respectively). In addition, the coexistence of high MACC1 and low NM23-H1 expression and tumor budding was associated with short OS (p < 0.001). We suggest that the combination of reduced NM23-H1, induced MACC1, and the presence of tumor budding are promising biomarkers for the prediction of recurrence and may aid the stratification of patients with stage II colon cancer for adjuvant chemotherapy.

Prguda-Mujic J, Milde-Langosch K, Mueller V, et al.
The Predictive Significance of Metastasis-Associated in Colon Cancer-1 (MACC1) in Primary Breast Cancer.
Ann Clin Lab Sci. 2018; 48(2):191-196 [PubMed] Related Publications
BACKGROUND: Metastasis-Associated in Colon Cancer-1(MACC1) was first identified as a transcriptional activator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis which is associated with poor clinical outcome in breast cancer patients. The aim of the present study was to further investigate the prognostic or predictive value of MACC1 expression in breast cancer.
MATERIALS AND METHODS: We analyzed the MACC1 expression in 105 primary breast cancer samples by Western-Blot analysis and immunohistochemistry.
RESULTS: A significant correlation of high MACC1 expression with shorter disease-free survival was found within the group of lymph-node-negative patients. Additionally, an association of high MACC1 expression and shorter disease-free survival was observed within estrogen receptor positive tumors and patients without adjuvant chemotherapy.
CONCLUSION: Our results support a biologic role and potentially open the perspective for the use of MACC1 as a prognostic marker for treatment decision in breast cancer patients.

Guo T, Zhao S, Li Z, et al.
Elevated MACC1 expression predicts poor prognosis in small invasive lung adenocarcinoma.
Cancer Biomark. 2018; 22(2):301-310 [PubMed] Related Publications
BACKGROUND: Patients with small (⩽ 2 cm) invasive lung adenocarcinoma are at high risk of poor prognosis and disease recurrence after complete surgical resection. Therefore, identification of high-risk individuals from these patients emerges as an urgent problem. Elevated MACC1 expression predicts a poor prognosis in multiple types of cancer that are independent of TNM staging. This study investigated the prognostic value of MACC1 expression in patients with small invasive lung adenocarcinoma.
OBJECTIVE: The current study aimed to evaluate the relationship between MACC1 expression in patients' tumor tissue and prognosis in small invasive lung adenocarcinoma.
METHODS: The records of 131 patients with small invasive lung adenocarcinoma who underwent complete surgical resection were reviewed. The MACC1 expression was detected by immunohistochemical staining in all specimens. Meanwhile, western blot and real-time quantitative PCR were used to examine the expression level of MACC1 in human lung adenocarcinoma cell lines. The effect of clinicopathological risk factors on patients' survival was analyzed using the Kaplan-Meier approach and multivariable Cox models.
RESULTS: Elevated MACC1 expression was observed in 53 (40.5%) specimens, and in A549, H358, H460 and H322 lung adenocarcinoma cell lines. MACC1 overexpression was associated with differentiation (P= 0.005) and blood vessel invasion (P= 0.001). Compared with low MACC1 expression, elevated MACC1 expression was associated with significantly shorter overall survival (odds ratio = 6.515; 95% confidence interval: 1.382-30.721; P= 0.018) and disease-free survival (odds ratio = 3.270; 95% confidence interval: 1.117-9.569; P= 0.031). Multivariate analyses demonstrated high MACC1 expression is an independent risk factor of worse overall survival (odds ratio = 5.684; 95% confidence interval: 1.145-28.210; P= 0.034) and disease-free survival (odds ratio = 4.667; 95% confidence interval: 1.372-15.877; P= 0.014).
CONCLUSION: MACC1 is an independent prognostic marker in patients with small invasive lung adenocarcinoma after complete surgical resection. Differential outcomes are associated with MACC1 expression level.

Zhao Y, Liu Y, Lin L, et al.
The lncRNA MACC1-AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated mRNA stability of MACC1.
Mol Cancer. 2018; 17(1):69 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metabolic plasticity has been increasingly thought to be a determinant of tumor growth and metastasis. MACC1, a transcriptional regulator of MET, was recognized as an oncogene in gastric cancer (GC); however, its transcriptional or post-translational regulation was not clear. We previously reported the metabolic role of MACC1 in glycolysis to promote GC progression. MACC1-AS1 is the antisense lncRNA of MACC1, yet its function was previously unknown.
METHODS: We profiled and analyzed the expression of MACC1-AS1 utilizing the TCGA database as well as in situ hybridization using 123 pairs of GC tissues and matched adjacent normal gastric mucosa tissues (ANTs). The biological role of MACC1-AS1 in cell growth and metastasis was determined by performing in vitro and in vivo functional experiments. Glycolysis and antioxidant capabilities were assayed to examine its metabolic function. Further, the specific regulatory effect of MACC1-AS1 on MACC1 was explored transcriptionally and post-transcriptionally.
RESULTS: MACC1-AS1 was shown to be expressed significantly higher in GC tissues than in ANTs, which predicted poor prognosis in GC patients. MACC1-AS1 promoted GC cell proliferation and inhibited cell apoptosis under metabolic stress. Mechanistically, MACC1-AS1 stabilized MACC1 mRNA and post-transcriptionally augmented MACC1 expression. Further, MACC1-AS1 was shown to mediate metabolic plasticity through MACC1 upregulation and subsequent enhanced glycolysis and anti-oxidative capabilities, and this was suggested to be coordinated by the AMPK/Lin28 pathway.
CONCLUSIONS: Elevated expression of MACC1-AS1 in gastric cancer tissues is linked to poor prognosis and promotes malignant phenotype upon cancer cells. MACC1-AS1 is elevated under metabolic stress and facilitates metabolic plasticity by promoting MACC1 expression through mRNA stabilization. Our study implicates lncRNA MACC1-AS1 as a valuable biomarker for GC diagnosis and prognosis.

Duan F, Jiang J, Song C, et al.
Functional long non-coding RNAs associated with gastric cancer susceptibility and evaluation of the epidemiological efficacy in a central Chinese population.
Gene. 2018; 646:227-233 [PubMed] Related Publications
AIM: To screen and validate the gastric cancer-associated long non-coding RNAs (lncRNAs) and their functional single nucleotide polymorphisms (SNPs).
METHODS: Based on case-control design, we select the differentially expressed lncRNAs by bioinformation tools and validate SNPs in lncRNAs genes in population. Attributable risk percentage (ARP) and population attributable risk percentage (PARP) were used to assess the effect of epidemiology.
RESULTS: Four lncRNAs with SNPs (lnc-EVX1-3:3 (rs1859168), lnc-MACC1-1:7 (rs3815254), lnc-AMFR-1:1 (rs4784659) and lnc-ZNF33B-2:1 (rs579501)) were selected to be validated in population. The unconditional multiple logistic regression based on the dominant (odds ratio, OR=0.64, 95%confidence interval, 95%CI: 0.47-0.86) and recessive genetic model (OR=1.77, 95%CI: 1.34-2.35) showed rs1859168 was significantly associated with lower risk of gastric cancer. The dominant (OR=0.42, 95%CI:0.31-0.57) and additive (OR=0.52, 95%CI:0.40-0.67) genetic model revealed that rs4784659 decreased the risk of gastric cancer. Similarly, the dominant (OR=0.72, 95%CI: 0.52-0.98) and additive (OR=0.73, 95%CI: 0.56-0.97) genetic model showed the individuals with rs579501 had reduced risk of gastric cancer. Whereas no statistical association between rs3815254 and gastric cancer. ARP and PARP for gastric cancer associated with rs1859168 in dominant model (56.25%, 33.05%), and in recessive model (43.50% and 29.37%). For rs4784659, ARP and PARP were 138.09% and 10.39% in dominant model, 92.31% and 8.76% in additive model. For rs579501, ARP and PARP were 38.89% and 4.03% in dominant model, 36.99% and 3.88% in additive model.
CONCLUSION: Our findings showed rs4784659, rs579501 and rs1859168 reduced the susceptibility of gastric cancer. From epidemiological perspective, the lncRNAs with SNPs attenuate the development of gastric cancer.

Hua FF, Liu SS, Zhu LH, et al.
MiRNA-338-3p regulates cervical cancer cells proliferation by targeting MACC1 through MAPK signaling pathway.
Eur Rev Med Pharmacol Sci. 2017; 21(23):5342-5352 [PubMed] Related Publications
OBJECTIVE: Aberrant expression of miR-338-3p has recently involved in the progression and development of various types of malignant tumors, but its role in the progression of cervical cancer remains unknown. This study aims to investigate the role of miR-338-3p/MACC1 axis in the progression of cervical cancer.
PATIENTS AND METHODS: MiR-338-3p and metastasis-associated in colon cancer 1 (MACC1) expression was determined in cervical cancer by quantitative real-time PCR (qRT-PCR). We explored the association of miR-338-3p expression with pathology and prognosis in cervical cancer patients. We explored the function of miR-338-3p and MACC1 on cell proliferation. A luciferase reporter assay was conducted to confirm the target gene of miR-338-3p in cervical cancer cells.
RESULTS: In the present work, our data showed that the expression of miR-338-3p was substantially decreased in cervical cancer tissues and associated with advanced FIGO stage, lymph node metastasis, depth of cervical invasion and poor overall survival. However, the MACC1 had an opposite expression. Mechanistically, we identified that MACC1 which acted as a functional downstream target for miR-338-3p. Furthermore, overexpression of miR-338-3p decreased expression of MACC1 in cervical cancer cells could significantly inhibit cervical cancer cell proliferation and induce cells apoptosis. Interestingly, miR-338-3p and MACC1 had proven to be involved in the progression of cervical cancer cells by regulating mitogen-activated protein kinase (MAPK) signaling pathway.
CONCLUSIONS: Our results suggested miR-338-3p/MACC1/MAPK regulatory pathway play an important role in the progression of cervical cancer.

Nair RM, Balla MM, Khan I, et al.
In vitro characterization of CD133
BMC Cancer. 2017; 17(1):779 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Retinoblastoma (Rb), the most common childhood intraocular malignant tumor, is reported to have cancer stem cells (CSCs) similar to other tumors. Our previous investigation in primary tumors identified the small sized cells with low CD133 (Prominin-1) and high CD44 (Hyaluronic acid receptor) expression to be putative Rb CSCs using flow cytometry (FSC
METHODS: The cultured Rb Y79 cells were evaluated for surface markers by flow cytometry and CD133 sorted cells (CD133
RESULTS: Rb Y79 cell line shared the profile (CD133, CD90, CXCR4 and ABCB1) of primary tumors except for CD44 expression. The CD133
CONCLUSIONS: This study validates the observation from our earlier primary tumor study that CSC properties in Rb Y79 cell line are endowed within the CD133

Wang J, Wang W, Cai H, et al.
MACC1 facilitates chemoresistance and cancer stem cell‑like properties of colon cancer cells through the PI3K/AKT signaling pathway.
Mol Med Rep. 2017; 16(6):8747-8754 [PubMed] Free Access to Full Article Related Publications
With regards to colon cancer, resistance to 5‑fluorouracil (5‑FU)‑based chemotherapy and cancer stem cells (CSCs) are considered important factors underlying therapy failure. Metastasis‑associated colon cancer 1 (MACC1) has been associated with poor prognosis and the promotion of metastasis within several types of cancer. However, the biological behavior of MACC1 in chemoresistance and CSC‑like properties remains unclear. In the present study, various methods including gene knockdown, gene overexpression, western blotting, quantitative polymerase chain reaction and MTT assay, have been adopted. According to the results of the present study, MACC1 was depleted in two colon cancer cell lines resistant to 5‑FU; subsequently, CSC‑like properties and 5‑FU sensitivity were investigated. Within 5‑FU‑resistant cells, cell death was facilitated by MACC1 knockdown. Furthermore, sphere formation and the expression levels of pluripotent markers, including cluster of differentiation (CD) 44, CD133 and Nanog were reduced due to MACC1 depletion. Additionally, it was indicated that the phosphoinositide 3‑kinase/protein kinase B signaling pathway may be associated with 5‑FU resistance and CSC‑like properties via MACC1.

Wu J, Zhang D, Li J, et al.
MACC1 induces autophagy to regulate proliferation, apoptosis, migration and invasion of squamous cell carcinoma.
Oncol Rep. 2017; 38(4):2369-2377 [PubMed] Related Publications
Metastasis-associated colon cancer-1 (MACC1) plays an important role in cancer development, but the role and mechansim of MACC1 in squamous cell carcinoma (ESCC) remain unclear. In this study, we found that MACC1 expression was increased in ESCC, and correlated with lymph node metastasis. MACC1 knockdown suppresed ESCC cell proliferation, metastasis and enchanced cell apoptosis. Moreover, MACC1 knockdown inhibited ESCC cell autophagy, and 3-methyladenine was able to rescue MACC1-induced malignant phenotype of ESCC cells. Furthermore, MACC1 knockdown inactivated AMPK-ULK1 signaling pathway, and metformin could rescue MACC1-induced autophagy in ESCC cells. Collectively, this study found that upregulation of MACC1 in ESCC was associated with lymph node metastasis of patients, and MACC1 regulated ESCC cell proliferation, apoptosis, migration and invasion mainly through AMPK-ULK1 induced autophagy.

Radhakrishnan H, Ilm K, Walther W, et al.
MACC1 regulates Fas mediated apoptosis through STAT1/3 - Mcl-1 signaling in solid cancers.
Cancer Lett. 2017; 403:231-245 [PubMed] Related Publications
MACC1 was identified as a novel player in cancer progression and metastasis, but its role in death receptor-mediated apoptosis is still unexplored. We show that MACC1 knockdown sensitizes cancer cells to death receptor-mediated apoptosis. For the first time, we provide evidence for STAT signaling as a MACC1 target. MACC1 knockdown drastically reduced STAT1/3 activating phosphorylation, thereby regulating the expression of its apoptosis targets Mcl-1 and Fas. STAT signaling inhibition by the JAK1/2 inhibitor ruxolitinib mimicked MACC1 knockdown-mediated molecular signatures and apoptosis sensitization to Fas activation. Despite the increased Fas expression, the reduced Mcl-1 expression was instrumental in apoptosis sensitization. This reduced Mcl-1-mediated apoptosis sensitization was Bax and Bak dependent. MACC1 knockdown also increased TRAIL-induced apoptosis. MACC1 overexpression enhanced STAT1/3 phosphorylation and increased Mcl-1 expression, which was abrogated by ruxolitinib. The central role of Mcl-1 was strengthened by the resistance of Mcl-1 overexpressing cells to apoptosis induction. The clinical relevance of Mcl-1 regulation by MACC1 was supported by their positive expression correlation in patient-derived tumors. Altogether, we reveal a novel death receptor-mediated apoptosis regulatory mechanism by MACC1 in solid cancers through modulation of the STAT1/3-Mcl-1 axis.

Guo T, Zhao S, Wang P, et al.
YB-1 regulates tumor growth by promoting MACC1/c-Met pathway in human lung adenocarcinoma.
Oncotarget. 2017; 8(29):48110-48125 [PubMed] Free Access to Full Article Related Publications
Aberrant overexpression of the transcription/translation factor Y-box-binding protein (YB-1) is associated with poor prognosis of lung adenocarcinoma, however the underlying mechanism by which YB-1 acts has not been fully elucidated. Here, we reported that inhibition of YB-1 diminished proliferation, migration and invasion of lung adenocarcinoma cells. Interestingly, we identified metastasis associated in colon cancer-1 (MACC1) as a target of YB-1. Depletion of YB-1 markedly decreased MACC1 promoter activity and suppressed the MACC1/c-Met signaling pathway in lung adenocarcinoma cells. Additionally, chromatin immunoprecipitation (ChIP) assay demonstrated that YB-1 bound to the MACC1 promoter. Moreover, YB-1 was positively correlated with MACC1, and both proteins were over-expressed in lung adenocarcinoma tissues. The Cox-regression analysis indicated that high YB-1 expression was an independent risk factor for prognosis in enrolled patients. Furthermore, depletion of YB-1 attenuated tumorigenesis in a xenograft mouse model and reduced MACC1 expression in tumor tissues. Collectively, our data suggested that targeting YB-1 suppressed lung adenocarcinoma progression through the MACC1/c-Met pathway and that the high expression of YB-1/MACC1 is a potential prognostic marker in lung adenocarcinoma.

Juneja M, Kobelt D, Walther W, et al.
Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1.
PLoS Biol. 2017; 15(6):e2000784 [PubMed] Free Access to Full Article Related Publications
MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription. Most importantly, in CRC-xenografted mice, lovastatin and rottlerin restricted MACC1 expression and liver metastasis. This is-to the best of our knowledge-the first identification of inhibitors restricting cancer progression and metastasis via the novel target MACC1. This drug repositioning might be of therapeutic value for CRC patients.

Wen L, Li Y, Jiang Z, et al.
miR-944 inhibits cell migration and invasion by targeting MACC1 in colorectal cancer.
Oncol Rep. 2017; 37(6):3415-3422 [PubMed] Related Publications
Dysfunction of microRNAs (miRNAs) is strongly proved to participate in the pathogenesis and tumorigenicity of colorectal cancer (CRC). miR-944 was reported to play either oncogenic or tumor suppressive roles in human cancers. A recent study reported that the levels of miR-944 in recurrent CRC patients were evidently lower than that in non-recurrent cases, suggesting that miR-944 may function as a tumor suppressive miRNA in CRC. Yet, the clinical value and biological function of miR-944 remain rarely known in CRC. In the present study, we present that miR-944 level in CRC tissues is notably reduced compared to matched non-cancerous specimens. Its decreased level is evidently correlated with malignant clinical parameters and poor prognosis of CRC patients. Accordingly, the levels of miR-944 were obviously downregulated in CRC cells. Ectopic expression of miR-944 in CRC cells prominently inhibits the migration and invasion of tumor cells, while miR-944 knockdown increased these effects of CRC cells. Mechanically, miR-944 negatively regulated the metastasis-associated in colon cancer-1 (MACC1) abundance in CRC cells. Herein, MACC1 was found to be a downstream molecule of miR-944 in CRC. An inversely correlation between miR-944 and MACC1 was confirmed in CRC specimens. Furthermore, restoration of MACC1 expression could abrogate the anti-metastatic effects of miR-944 on CRC cells with enhanced cell migration and invasion. MACC1/Met/AKT signaling may be implicated with the function of miR-944 in CRC cells. Altogether, miR-944 potentially act as a prognostic predictor and a drug-target for CRC patients.

Rohr UP, Herrmann P, Ilm K, et al.
Prognostic value of MACC1 and proficient mismatch repair status for recurrence risk prediction in stage II colon cancer patients: the BIOGRID studies.
Ann Oncol. 2017; 28(8):1869-1875 [PubMed] Related Publications
Background: We assessed the novel MACC1 gene to further stratify stage II colon cancer patients with proficient mismatch repair (pMMR).
Patients and methods: Four cohorts with 596 patients were analyzed: Charité 1 discovery cohort was assayed for MACC1 mRNA expression and MMR in cryo-preserved tumors. Charité 2 comparison cohort was used to translate MACC1 qRT-PCR analyses to FFPE samples. In the BIOGRID 1 training cohort MACC1 mRNA levels were related to MACC1 protein levels from immunohistochemistry in FFPE sections; also analyzed for MMR. Chemotherapy-naïve pMMR patients were stratified by MACC1 mRNA and protein expression to establish risk groups based on recurrence-free survival (RFS). Risk stratification from BIOGRID 1 was confirmed in the BIOGRID 2 validation cohort. Pooled BIOGRID datasets produced a best effect-size estimate.
Results: In BIOGRID 1, using qRT-PCR and immunohistochemistry for MACC1 detection, pMMR/MACC1-low patients had a lower recurrence probability versus pMMR/MACC1-high patients (5-year RFS of 92% and 67% versus 100% and 68%, respectively). In BIOGRID 2, longer RFS was confirmed for pMMR/MACC1-low versus pMMR/MACC1-high patients (5-year RFS of 100% versus 90%, respectively). In the pooled dataset, 6.5% of patients were pMMR/MACC1-low with no disease recurrence, resulting in a 17% higher 5-year RFS [95% confidence interval (CI) (12.6%-21.3%)] versus pMMR/MACC1-high patients (P = 0.037). Outcomes were similar for pMMR/MACC1-low and deficient MMR (dMMR) patients (5-year RFS of 100% and 96%, respectively).
Conclusions: MACC1 expression stratifies colon cancer patients with unfavorable pMMR status. Stage II colon cancer patients with pMMR/MACC1-low tumors have a similar favorable prognosis to those with dMMR with potential implications for the role of adjuvant therapy.

Tokarz P, Pawlowska E, Bialkowska-Warzecha J, Blasiak J
The significance of DNA methylation profile in metastasis-related genes for the progression of colorectal cancer.
Cell Mol Biol (Noisy-le-grand). 2017; 63(2):79-87 [PubMed] Related Publications
DNA methylation, an epigenetic modification plays a role in the pathogenesis of colorectal cancer (CRC). CRC cases, both sporadic and familial, are often characterized by abnormal pattern of the cytosine methylation in CpG dinucleotides in regulatory regions of genes important for cancer transformation. Also genes mutated in CRC can have their epigenetic pattern altered and we suggest that changes in DNA methylation array can be important for CRC metastatic potential ‒ the main reason of CRC-associated mortality. These genes are: KRAS, genes of the Rho family of GTPases, MACC1, Met, MTA1 and RASSF1A. In addition, genes encoding miRNA important for epithelial mesenchymal transition and other metastasis-related effects, such as mir-9, miR-34 and miR-210 can be good candidates for associating their DNA methylation profiles with CRC metastasis. Analysis of DNA methylation profile in various stages of CRC along with other genetic/epigenetic changes specific for all main stages of CRC transformation could help in anti-metastatic therapy immediately after CRC diagnosis. However, targeting DNA methylation pattern in CRC therapy is a conception, which requires further work to precisely change DNA methylation array, without affecting genes, whose expression should not be changed.

Duan J, Chen L, Zhou M, et al.
MACC1 decreases the chemosensitivity of gastric cancer cells to oxaliplatin by regulating FASN expression.
Oncol Rep. 2017; 37(5):2583-2592 [PubMed] Free Access to Full Article Related Publications
The effect of chemotherapeutic agents is limited as a result of drug resistance, which demands prompt solutions provided by clinical studies. To date, the underlying mechanisms of chemotherapy resistance are relatively unknown. Metastasis-associated in colon cancer 1 (MACC1) is an oncogene associated with the progression and prognosis of gastric cancer (GC). Bioinformatic analysis revealed that MACC1 is positively associated with fatty acid synthase (FASN), a major enzyme of lipogenesis, and drives chemoresistance to oxaliplatin in GC. Similar findings were demonstrated in two GC cell lines (BGC-823 and MKN-28) with MACC1 ectopic expression. We next employed FASN inhibitor C75 or siFASN (small interfering RNA targeted to FASN) to block endogenous fatty acid metabolism and it was revealed that cell proliferation and chemoresistance to oxaliplatin induced by MACC1 upregulation were attenuated by FASN blockade to various extents. Conclusively, these outcomes highlight a novel role of MACC1 in GC cell lipogenesis, and suggest that MACC1 may be an attractive target to decrease oxaliplatin resistance in GC.

Wang C, Wen Z, Xie J, et al.
MACC1 mediates chemotherapy sensitivity of 5-FU and cisplatin via regulating MCT1 expression in gastric cancer.
Biochem Biophys Res Commun. 2017; 485(3):665-671 [PubMed] Related Publications
Chemotherapeutic insensitivity is a main obstacle for effective treatment of gastric cancer (GC), the underlying mechanism remains to be investigated. Metastasis-associated in colon cancer-1 (MACC1), a transcription factor highly expressed in GC, is found to be related to chemotherapy sensitivity. Monocarboxylate transporter 1 (MCT1), a plasma membrane protein co-transporting lactate and H

Chen S, Zong ZH, Wu DD, et al.
The role of metastasis-associated in colon cancer 1 (MACC1) in endometrial carcinoma tumorigenesis and progression.
Mol Carcinog. 2017; 56(4):1361-1371 [PubMed] Related Publications
Metastasis-associated in colon cancer-1 (MACC1), has recently been identified as a key regulator in the progression of many cancers. However, its role in endometrial carcinoma (EC) remains unknown. MACC1 expression was determined in EC and normal endometrial tissues by immunohistochemistry. EC cell phenotypes and related molecules were examined after MACC1 downregulation by Small interfering RNA (siRNA) or microRNA (miRNA) transfection. We found that MACC1 was highly expressed in EC tissues than normal samples, and was significantly different in FIGO staging (I and II vs. III and IV), the depth of myometrial infiltration (<1/2 vs. ≥1/2), lymph nodes metastasis (negative vs. positive), besides, MACC1 overexpression was correlated with lower cumulative and relapse-free survival rate. MACC1 downregulation by siRNA transfection significantly induced G1 phrase arrest, suppressed EC cell proliferation, migration, and invasion. In addition, MACC1 downregulation also reduced expression of Cyclin D1 and Cyclin-dependent Kinase 2 (CDK2), N-cadherin (N-Ca), α-SMA, matrix metalloproteinase 2 (MMP2), and MMP9, but increased expression of E-cadherin (E-Ca). Bioinformatic predictions and dual-luciferase reporter assays indicate that MACC1 is a possible target of miR-23b. MiR-23b overexpression reduced MACC1 expression in vitro and induced G1 phrase arrest, suppressed cell proliferation, migration, and invasion. MiR-23b transfection also reduced Cyclin D1 and CDK2, N-Ca, α-SMA, MMP2, MMP9 expression, but increased E-Ca expression. Furthermore, the nude mouse xenograft assay showed that miR-23b overexpression suppressed tumour growth through downregulating MACC1 expression. Taken together, our results demonstrate for the first time that MACC1 may be a new and important diagnosis and therapeutic target of endometrial carcinoma.

Evran E, Şahin H, Akbaş K, et al.
Investigation of MACC1 Gene Expression in Head and Neck Cancer and Cancer Stem Cells.
Clin Invest Med. 2016; 39(6):27506 [PubMed] Related Publications
PURPOSE: By investigating the MACC1 gene (metastasis-associated in colon cancer 1) in cancer stem cells (CSC) resistant to chemotherapy and in cancer stem cells (CSC) resistant to chemotherapy and in cancer cells (CS) sensitive to chemotherapy we determineda steady expression in both types of cells in head and neck cancer. In conformity with the result we examined if this gene could be a competitor gene for chemotherapy. According to literature, the MACC1 gene shows a clear expression in head and neck cancer cells [1]. Here we examined MACC1 expression in CSC and investigated it as a possible biomarker.
METHODS: Our experiments were performed in the UT -SCC -74 in primary head and neck cancer cell line. We examined the MACC -1 gene expression by Real Time PCR from both isolated CSC and CS.
RESULTS: Expression of MACC -1 gene of cancer stem cells showed an two-fold increase compared with cancer cells. Based on the positive expression of MACC1 in both CS and CSC, this gene may serve as a potential biomarker in head and neck cancer. By comparing the results of this study with the novel features of MACC1, two important hypotheses could be examined. The first hypothesis is that MACC1 is a possible transcripton factor in colon cancer, which influences a high expression of CSC in head and neck and affects the expression of three biomarkers of the CSC control group biomarkers. The second hypothesisis is that the positive expression of MACC1 in patients with a malignant prognosis of tongue cancer, which belongs to head and neck cancer types, operates a faster development of CSC to cancer cells.

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